The long-term goal of this project is to identify specific serotonin receptor subtypes which may play a role in peripheral inflammatory pain states. Through a cooperative research effort between Spectra Biomedical Inc. and University of California, San Francisco both PCR techniques (Spectra) and a rat model of plasma extravasation (UCSF) will be used to achieve this goal. Specifically, PCR techniques will be used to identify the presence of mRNA for various 5-HT receptor subtypes in both rat and human dorsal root ganglia neurons. The objective of this experiment is to determine which 5-HT receptor types are expressed in these neurons and therefore indicate which receptors might be available for modulating peripheral nociceptive transmission. This information will be used to investigate the role of 5-HT receptor subtypes in peripheral inflammation in the model of plasma extravasation (PE) in the rat knee joint. In this model, rats are injected through the tail vein with Evans blue dye (which attaches to intravascular proteins) and the amount of dye recovered from a perfusate of the knee joint is then used as an indicator of the degree of PE. Capsaicin which excites and induces the release of neuropeptides from C-fiber terminals will be used to elicit PE. The sympathetic neuron excitotoxin 6- hydroxydopamine will also be used to elicit PE due to activation of sympathetic post-ganglionic efferents. In addition, neonatal rats will be treated with capsaicin to destroy C-fibers to determine if 5-HT-induced PE in adulthood is mediated via C-fiber activation. 5-HT and selective 5-HT agonists and antagonists will be tested for the role of C-fiber afferent and sympathetic efferent neurons in this process. The ability of selective 5-HT agents to modulate PE in a model of chronic peripheral pain (spinal nerve ligation) will also be tested. Results from these studies will potentially lead to commercialization of novel therapeutic agents for the treatment of inflammatory pain states.